Submissions for variant NM_000441.2(SLC26A4):c.554G>C (p.Arg185Thr)

gnomAD frequency: 0.00003  dbSNP: rs542620119

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000169232	SCV001428425	likely pathogenic	Pendred syndrome	2020-06-24	reviewed by expert panel	curation	The c.554G>A (p.Arg185Thr) variant in SLC26A4 was present in 0.03287% (1/3042) of South Asian alleles in gnomAD v3, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined for autosomal recessive hearing loss by the ClinGen Hearing Loss Expert Panel (PM2_Supporting; gnomad.broadinstitute.org). This variant has been identified in one individual with unilateral hearing loss and enlarged vestibular aqueduct with a second likely pathogenic variant in trans, as well as two probands without a second variant identified but whose phenotypes were consistent with Pendred syndrome (PM3, PP4; PMID: 24051746, 20597900, 22285650). It was also observed in one proband with limited phenotype information and no second variant identified (PMID: 31387071). Functional evidence demonstrates that the p.Arg185Thr variant may impact protein function (PS3_Supporting, PMID: 22285650, 24051746). The REVEL computational prediction tool produced a score of 0.876, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3, PS3_Supporting, PM2_Supporting, PP3, PP4.
Counsyl	RCV000169232	SCV000220501	likely pathogenic	Pendred syndrome	2014-07-10	criteria provided, single submitter	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214962	SCV000271454	pathogenic	Rare genetic deafness	2016-01-04	criteria provided, single submitter	clinical testing	The p.Arg185Thr variant in SLC26A4 has been previously reported in three individ uals with hearing loss and enlarged vestibular aqueducts, including one individu al who was compound heterozygous for a second pathogenic variant in the SLC26A4 gene (Chattaraj 2013, Cirello 2012, Pourova 2010). This variant has been identif ied in 12/66734 (0.02%) of European chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs542620119); however, this fre quency is low enough to be consistent with a recessive carrier frequency. In vit ro functional studies reveal that the variant results in abnormal cellular local ization of the protein and significant reduction in its normal functional activi ty (Cirello 2012, Chattaraj 2013), supporting a deleterious effect for this vari ant. In addition, computational tools and conservation analyses predict that the p.Arg185Thr variant may impact the protein. In summary, this variant meets our criteria to be classified as pathogenic.
SIB Swiss Institute of Bioinformatics	RCV000677335	SCV000803604	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for DFNB4, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Supporting => PS3 downgraded in strength to Supporting (PMID:22285650). PM2-Supporting => PM2 downgraded in strength to Supporting. PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:24051746).
Illumina Laboratory Services, Illumina	RCV000778810	SCV000915190	likely pathogenic	SLC26A4-Related Disorders	2018-08-15	criteria provided, single submitter	clinical testing	The SLC26A4 c.554G>C (p.Arg185Thr) variant is a missense variant that has been reported in a total of three individuals with nonsyndromic hearing loss or Pendred syndrome, including in a compound heterozygous state in one and in a heterozygous state in two (Pourova et al. 2010; Cirello et al. 2012; Chattaraj et al. 2013). One of the heterozygotes was also heterozygous for a missense variant in the FOXI1 gene, which is said to display digenic inheritance with SLC26A4. The p.Arg185Thr variant is reported at a frequency of 0.000180 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in COS-7 cells, HEK293 phoenix cells and Xenopus oocytes have demonstrated the variant results in a trafficking defect, altered maturation, and reduced function compared to wildtype. Based on the collective evidence, the p.Arg185Thr variant is classified as likely pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital	RCV000169232	SCV001792214	pathogenic	Pendred syndrome		criteria provided, single submitter	research	in compound heterozygosis with the c.412G>T variant in a subject with bilateral non-syndromic sensorineural prelingual hearing loss (sporadic)
Invitae	RCV001850394	SCV002243689	pathogenic	not provided	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 185 of the SLC26A4 protein (p.Arg185Thr). This variant is present in population databases (rs542620119, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Pendred syndrome (PMID: 20597900, 22285650, 24051746, 31387071, 34599368). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188878). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 22285650, 24051746). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002498842	SCV002810544	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2021-10-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169232	SCV003928981	pathogenic	Pendred syndrome	2023-04-04	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.554G>C (p.Arg185Thr) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251456 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (9.1e-05 vs 0.0035), allowing no conclusion about variant significance. c.554G>C has been reported in the literature in individuals affected with clinical features of Pendred Syndrome (example, Pourova_2010, Cirello_2012, Chattaraj_2013, Lenarduzzi_2019, Batissoco_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in predominantly intracellular localization and a partial glycosylation defect resulting in impaired chloride and iodide ion transport in-vitro (example, Cirello_2012, Chattaraj_2013). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (LP/P, n=5; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000677335	SCV004201821	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-10-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001850394	SCV004238663	likely pathogenic	not provided	2023-05-23	criteria provided, single submitter	clinical testing